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At least 19 recordsLinked to original sources
PubMed2025

Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.

Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.

Humans↗
PubMed2026

Genetically Predicted Gene Expression and Circulating Metabolites Associated with Cervical High-Grade Squamous Intraepithelial Lesion: A Mendelian Randomization Study.

BACKGROUND: High-grade squamous intraepithelial lesion (HSIL) is a precancerous condition of the cervix. Identifying risk factors associated with HSIL and understanding their potential mechanisms may inform prevention strategies. This study aimed to investigate the associations of genetically predicted gene expression and circulating metabolites with HSIL risk using Mendelian randomization (MR). METHODS: We performed two-sample MR analysis to evaluate the associations of genetically predicted gene expression (eQTLGen consortium, N=31,684) and circulating metabolites (genome-wide association study [GWAS], N=8,299) with HSIL risk (FinnGen R12, N=293,218; 8,291 cases). Mediation analysis was conducted to explore whether metabolites might mediate the associations between genes and HSIL. Sensitivity analyses, including Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out, and colocalization, were performed to assess the robustness of the findings. All GWAS data used in this study were derived from European-ancestry populations. RESULTS: Eleven genes showed significant associations with HSIL after false discovery rate (FDR) correction (q<0.05), including VWA7, PAX8, GUSBP1, IKZF3, PAX8-AS1, NFKBIL1 (interpret with caution due to an influential single nucleotide polymorphism [SNP]), ERBB2, COL11A2, SKIV2L, TCF19, and PGAP3. Eleven circulating metabolites were also significantly associated with HSIL. Mediation analysis suggested that two phospholipid metabolites (GCST90200685 and GCST90200692) might mediate a small proportion of the total protective association of COL11A2 with HSIL (1.46% and 1.45%, respectively), indicating that the protective association of COL11A2 is largely independent of these circulating metabolites. Colocalization analysis showed strong evidence of shared causal variants for eight genes (PP.H4>0.98), while COL11A2 showed weak evidence of colocalization (PP.H4=1.58&#xd7;10-15). Functional enrichment analysis indicated that COL11A2-related genes were enriched in extracellular matrix (ECM)-receptor interaction and PI3K-Akt signaling pathways. CONCLUSION: This MR study identified 11 genes and 11 circulating metabolites associated with HSIL risk. Among these, COL11A2 showed a protective association that appeared to be largely independent of circulating phospholipid metabolites, suggesting potential local mechanisms. These findings provide genetic and metabolic clues for future studies on HSIL etiology.

COL11A2↗
PubMed1977

Use of octadecasilyl-silica for the extraction and purification of peptides in biological samples. Application to the identification of circulating metabolites of corticotropin-(1-24)-tetracosapeptide and somatostatin in vivo.

Peptides can be adsorbed on octadecasilyl-silica from large volumes of aqueous solution and eluted with aqueous solvent mixtures containing methanol or acetonitrile. These properties may be used for the extraction and purification of peptide fragments in plasma samples collected from rats. After intravenous injection of Synacthen [corticotropin-(1-24)-tetracosapeptide], it was shown that within 2 min the main circulating products were intact peptide and its sulphoxide. In addition, a number of fragments indicative of cleavage at the N- and C-termini were present. Most of the products formed from Synacthen have low biological activity. Somatostatin was rapidly cleaved in vivo and in vitro to a single product, which probably retains biological activity. The absence of other circulating products suggests that somatostatin is only inactivated once it leaves the circulation.

Adrenocorticotropic Hormone↗
PubMed2026

Association of Genetic Liability to Psychiatric Disorders with Peripheral Metabolic Dysregulation.

IMPORTANCE: Individuals with psychiatric disorders face elevated cardiometabolic risk which is linked to increased mortality. The extent to which this reflects shared pathogenesis or the downstream effects of illness and treatment remains poorly understood. OBJECTIVE: To characterize the direct pleiotropic effects of psychiatric genetic liability on circulating metabolites and aggregate cardiometabolic risk, independent of psychiatric diagnosis and psychotropic medication use. DESIGN SETTING AND PARTICIPANTS: Cross-sectional analysis of Mass General Brigham Biobank participants with metabolomic profiling, genomic data, and linked electronic health records. EXPOSURES: Genetic liability to nine psychiatric disorders quantified using polygenic risk scores (PRS): attention deficit/hyperactivity disorder (ADHD), anorexia nervosa (ANO), anxiety disorder (ANX), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), PTSD, schizophrenia (SCZ), and substance use disorder (SUD). MAIN OUTCOMES AND MEASURES: 249 circulating metabolites and four metabolomic risk scores (MRS) for type 2 diabetes, myocardial infarction, ischemic stroke, and vascular dementia. PRS-metabolite associations were estimated using nested models adjusting for lifetime psychiatric diagnosis and psychotropic medication use. RESULTS: Across 25,290 participants, we identified 604 significant PRS-metabolite associations (Bonferroni p< 1.36 x 10-4), of which 89% persisted after adjustment for lifetime diagnosis and medication use, suggesting that the direct genetic effects on metabolism are largely independent of illness or treatment. PRS for MDD, PTSD, and ADHD showed the most extensive dysregulation, with a transdiagnostic pattern of elevated lipids and systemic inflammation, specifically triglycerides (&#x3b2; = 0.04 to 0.05, all p< 4.4 x10-13) and glycoprotein acetyls (&#x3b2; = 0.05, all p< 2.2 x10-16). Notably, PRS for SCZ and BD showed minimal metabolite dysregulation despite having the strongest association with their target diagnoses. PRS for MDD, PTSD, ADHD, and SUD were associated with increased MRS across cardiometabolic conditions (&#x3b2; = 0.03 to 0.08, all p< 2.1 x10-4). Sensitivity analyses controlling for BMI or excluding participants without any psychiatric history (N: 21,305 and 11,150, respectively) showed a similar pattern. CONCLUSIONS AND RELEVANCE: Psychiatric genetic liability is associated with systemic metabolic dysregulation independent of illness onset or treatment, supporting a partially pleiotropic basis for psychiatric-cardiometabolic comorbidity.

Journal Article↗
PubMed1976

Uptake and release of hormones and metabolites by tissues of exercising leg in man.

To examine release of insulin from tissues of the exercising llin, growth hormone, cortisol, and circulating metabolites were studied in five men before, during, and after exercise on a bicycle ergometer at 60% of their maximum work capacity. At rest, insulin, growth hormone, and cortisol were taken up by leg tissues. During exercise arterial plasma insulin concentration fell, but cortisol and growth hormone levels rose; there was net release of insulin into venous blood but little change in uptake of cortisol and growth hormone. Insulin release persisted after exercise for 15-30 min. During exercise arterial concentrations and uptake of glucose and free fatty acids (FFA) increased. Examination of the changes in hormones and metabolites failed to identify any single hormonal or metabolic factor causing the observed reversal of insulin uptake with exercise.

Adult↗
PubMed1976

Propoxyphene: pathways of metabolism in man and laboratory animals.

Through the combined use of stable isotope labeling and gas chromatographic mass spectrometric analysis, the metabolic patterns for propoxyphene have been determined in laboratory animals and man. The rat and dog eliminated propoxyphene and its metabolites principally via the bile, while the rabbit more closely resembled man in excreting the metabolic products into urine. Metabolites in rat and rabbit existed as conjugates, whereas in dog and man the metabolites were excreted as a mixture of the free and unconjugated forms. The primary route of metabolism in all species studied was N-demethylation. However, the rat and rabbit extensively hydroxylated propoxyphene and its metabolites prior to elimination. Metabolites arising from ester hydrolysis were found in rat and man. N-acetylated products were identified in all four species. A metabolite formed from cyclization and dehydration of dinorpropoxyphene was isolated in urine and was further identified as a circulating metabolite in dog plasma.

Acetylation↗
PubMed1977

Physiologic disposition of nabilone, a cannabinol derivative, in man.

Nabilone is a cannabinoid that is being evaluated in man as a potentially useful psychoactive drug. We found that nabilone was readily absorbed from the human gastrointestinal tract when administered orally as a coprecipitate with polyvinyl-pyrrolidone. The absorbed drug disappeared from plasma rather rapidly (half-life, approximately 2 hr), evidently due to extensive tissue distribution and rapid metabolism. The metabolites of nabilone persist in plasma for extended periods (half-life of total radioactivity exceeds 20 hr). Circulating metabolites include isomeric carbinols formed by reduction of the ketone in the 9-position of nabilone. Nabilone is eliminated in feces (about 65% of dose) and urine (20%). The excretory products in urine have not been identified, but metabolites that are labile to hydrolysis by beta-glucuronidase or sulfatase do not appear to be formed in significant amounts. A metabolite of nabilone in feces has been identified as a diol formed by reduction of the 9-keto group plus oxidation at the penultimate carbon of the dimethylheptyl side chain. The long duration of action of nabilone in the face of rapid and extensive metabolic elimination suggests that the pharmacologic effects, at least in part, may be exerted by one or more active metabolites.

Administration, Oral↗
PubMed1976

Intestinal absorption and biliary excretion kinetics of 14C-labeled methadone in the rat.

Intestinal abosrption, biliary excretion and enterohepatic circulation of d,l-methadone were studied in male, female, fasted and fed rats by monitoring the appearance of radioactivity in the portal vein, the inferior vena cava, and the bile following intraduodenal administration of 2-14C-d,l-methadone. An early peak in portal concentration was not reflected in the peripheral blood or in the bile. An enterohepatic circulation exists, but is minimal, accounting for less than 1% of the dose in the first hr. Experimental diversion of the bile flow from the lumen of the duodenum has little effect on the relative percentage of methadone vs. metabolites circulating in the blood. However, bile diversion was associated with a 2 to 3 fold increase in the concentration of methadone and its metabolites in portal and peripheral blood 30 min following administration. Eighty to 90% of the 14C in the portal blood is present as methadone and 60 to 70% of the 14C in peripheral blood is methadone while less than 10% of the radioactive materials in the bile is methadone. The amount of metabolite No. 1, metabolite No. 2 and water soluble metabolites vary with over 60% of the radioactive compounds in recirculated bile in the form of water soluble materials.

Animals↗
PubMed2024

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. CONCLUSION: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Humans↗
PubMed2026

Metabolites with a message: impacts on epigenetics and implications for epimetabopathies.

Once identified primarily as a bioenergetic organelle, the mitochondrion has now emerged as a pivotal signalling hub that communicates with the nucleus to shape cellular fate. It integrates the cell's metabolic state with transcriptional and epigenetic programs, tweaking gene expression. Mitochondrial metabolites serve as regulators of cellular physiology, functioning as important signalling intermediates and modulating enzymes involved in epigenetic modifications. In parallel, nuclear transcriptional programs govern mitochondrial biogenesis, dynamics and quality control to preserve metabolic homeostasis under stress. Moreover, circulating metabolites can function as systemic messengers coordinating interorgan crosstalk and immune responses. Perturbations in this dynamic reciprocity can rewire the cellular script and spiral into "epimetabopathies", where metabolic-epigenetic conflicts ignite pathological conditions. This review discusses how mitochondria-nucleus crosstalk coordinates genome surveillance, metabolite-driven epigenetic regulation and systemic metabolic signalling. It further offers an overview of epimetabopathies with potential implications for future diagnostics and therapeutics.

Humans↗
PubMed1976

The distribution and clearances of hormones and metabolites in the circulation of the foetal sheep.

Plasma hormone and metabolite concentrations have been measured in the plasma of blood collected simultaneously from the femoral artery, umbilical vein and carotid artery of the exteriorized foetal sheep. The concentration of vasopressin and catecholamines was consistently lower and of glucose, lactate and corticosteroids consistently higher in the umbilical vein compared with the femoral artery. ACTH concentrations showed no consistent pattern and fluctuated widely at each site, but during synacthen infusion the concentration in the umbilical vein was consistently lower than in the femoral artery. For corticosteroids the concentration in the carotid artery was much lower than that in the umbilical vein; the converse was true for catecholamines. Concentrations in the carotid and femoral artery were similar for all compounds investigated. These results indicate that the placenta is a major site of vasopressin, catecholamine and ACTH clearance and of glucose, lactate and corticosteroid production. The foetal liver is probably a major site of corticosteroid and catecholamine clearance.

Adrenocorticotropic Hormone↗
PubMed1977

Signals for glucagon secretion.

The normal physiological role of glucagon is in controlling hepatic glucose output. Glucagon subserves the role of homeostasis by maintaining plasma glucose and of a stress hormone by producing hyperglycaemia. While control of glucagon release by circulating metabolites and also other hormones is clearly important, it seems likely that the nervous system exerts an over-riding influence. The parasympathetic nervous system maintains homeostasis and the sympathetic acts in stress. Glucagon levels are found to be high in cirrhosis and also after acute hepatic failure. It is likely that these changes in glucagon concentration are secondary to metabolic abnormalities. While some glucagon is cleared by the liver, a similar clearance is seen by many other tissues and it is not likely that the elevation of glucagon seen in liver failure is due solely to a gross deficiency of glucagon clearance. No liver abnormality is seen in the glucagonoma syndrome, where glucagon concentration are chronically high, or in patients who have had a total pancreatectomy, where plasma glucagon is undetectably low. It thus seems unlikely that liver mass is importantly controlled by glucagon.

Adrenalectomy↗
PubMed1978

Physiologic disposition of lergotrile.

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea-amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinson's disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N-14CH3-lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was attributed to the presence of circulating metabolites of lergotrile. Lergotrile metabolities were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13-OH-lergotrile (up to 30% of the dose). A metabolite in urine was formed by conversion of the C8-acetonitrile group of lergotrile to a carboxyl group (about 10% of the dose). The presence of 14CO2 in the expired air after administering N-14C-methyl-lergotrile indicated that the drug was N-demethylated to form norlergotrile.

Acetonitriles↗
PubMed1976

Blood sampling techniques for studying rapidly turning over metabolic fuels in mice.

Experiments were carried out in control and Ehrlich ascites carcinomatous mice to determine whether orbital venous sinus blood could be used to reflect blood in the systemic circulation (decapitation blood) in the case of a rapidly turning over metabolic fuel such as free fatty acids. The early time course of intravenously injected, labeled free fatty acids was measured using (9, 10-(3)H) palmitic acid and (1-(14)C) linoleate complexed to mouse serum. No significant differences between decapitation and orbital sinus blood were found at early times in either group of mice. The orbital sinus clearly contains blood that is not stagnant and is replaced so rapidly that it is suitable for studying very rapidly turning over, circulating metabolites.

Animals↗
PubMed1978

Specific production of prostaglandin E by human amnion in vitro.

Prostaglandin production by intra-uterine human tissues has been investigated using a method of tissue superfusion. Tissues were obtained at elective Caesarean section and after spontaneous vaginal delivery. It was found that all the tissues studied (amnion, chorion, decidua and placenta) produced more prostaglandin E (PGE) and 13,14-dihydro-15-keto-prostaglandin F (PGFM - the major circulating metabolite of prostaglandin F) than prostaglandin F (PGF). Amnion produced significantly more PGE (but not PGF or PGFM) than any other tissue. Prostaglandin production by each tissue was similar whether it was taken at elective Caesarean section or after spontaneous vaginal delivery.

Amnion↗
PubMed1979

Applications and limitations of measurement of 15-keto,13,14-dihydro prostaglandin E2 in human blood by radioimmunoassay.

It has been anticipated that the inherent limitations of radioimmunoassays for prostaglandin E (PGE) would be obviated by assays for its major circulating metabolite, 15-keto, 13,14-dihydro PGE2) which has a longer half-life in blood. We examined the effects of PGE2 infusion and alterations in lipolysis in vivo, and of clotting, prolonged storage and hemolysis in vitro, on KH2-PGE2 immunoreactivity in unextracted human plasma and serum samples. Indeed KH2-PGE2 levels rose several hundred fold during infusions of PGE2 at doses which cause little or no increment in peripheral PGE levels. During stimulation of lipolysis by infusions of epinephrine, apparent KH2-PGE2 levels rose five-fold. However, the dilution curve of plasma obtained during stimulation of lipolysis was not parallel to the standard curve; furthermore, apparent KH2-PGE2 levels were correlated strongly with free fatty acid (FFA) levels, suggesting that FFA's cross-reacted in the RIA weakly but significantly due to their very high molar concentration in blood. Clotting and prolonged storage of samples, but not hemolysis, also caused marked apparent increments in KH2-PGE2 levels. Competition curves using dilutions of such samples were again not parallel to the standard curves in plasma or buffer, but resembled dilution curves of samples containing high levels of FFA. These results suggest that handling of human blood samples for KH2-PGE2 measurement must be carefully standardized to avoid significant artifacts which presumably are due in part to fatty acids released from triglyceride stores in vivo or from disrupted membrane phospholipids in vitro. Unextracted plasma appears to be unsatisfactory for use in this RIA.

Adult↗
PubMed2026

Epigenetic regulation of fatty acid chain elongation in MAFLD and its implications in the liver-brain axis dysfunction.

Lipid metabolism plays a crucial role in cellular health and physiology by acting as an energy storehouse, cell membrane component, brain development and signaling molecules. Crucial steps to metabolize dietary fat take place within the hepatic tissue. Any abnormalities in the hepatic fatty metabolic pathways cause abnormal accumulation of lipid inside the liver, causing MAFLD, ranging from simple steatosis to more complex steatohepatitis and fibrosis. During high-fat-diet-induced hepatic inflammation, systemic proinflammatory cytokines disrupt the blood-brain barrier, resulting in neuroinflammation, cognitive impairment, brain damage and even neurodegeneration. Further, during this altered metabolic scenario, circulating metabolites pass through the impaired BBR and deregulate the epigenetic landscape of the central nervous system. Thus, it becomes crucial to understand the epi-metabolic crosstalk between two crucial organs of our body: the liver and the brain. Here in this chapter, we demonstrate the approach that we are using in our laboratory to study the epigenetic reprogramming in the context of metabolic gene expression in the liver, which is the causal for life style disorders like MAFLD. Remarkably, we intend to understand how liver dysfunction can have an implication in the brain function. Here, we discuss the concept of developing a diet-induced steatosis and steatohepatitis mouse model to understand the disease progression and its interconnection with brain physiology. Further, we also demonstrate 2D and 3D cell culture models to study the liver-brain cross-talk in greater molecular detail. Collectively, these approaches can provide a template for studying the role of epi-metabolic cross-talk in liver-guided brain dysfunction upon MAFLD.

Animals↗